Alzheimer's Drug Pipeline: Past, Present, and Future Biologic Therapies

Alzheimer's disease (AD) is the most common type of dementia. This is a progressive neurodegenerative disorder, whereby cognitive and social abilities deteriorate over time and functioning suffers. In the United States alone, 6.5 million individuals aged 65 and older have AD with 70% being 75 years old or older. The prevalence of AD is believed to be between 60 and 70% among the 55 million persons with dementia globally¹. This debilitating disease is characterized by a decades-long accumulation of amyloid protein plaques in the brain, leading to neuronal damage and ultimately death. Patients with AD may display personality changes, inappropriate conduct, memory loss, communication difficulties, trouble learning or remembering new information, and planning difficulties.

AD’s pathophysiology is characterized by both the aforementioned neurotic plaques (clusters of beta-amyloid protein) as well as neurotic tangles (tau protein accumulation). The latter is the presence of hyperphosphorylated neurofibrillary tau tangles within the cell that may be a responds to former, amyloid beta². The Amyloid Precursor Protein (APP) is a transmembrane protein that supports the development and maintenance of synapses. If APP is proteolytically cleaved by beta- then gamma-secretases, opposed to alpha- then gamma-, the undesired amyloid beta (Aβ) is produced². These 40 – 42 amino acid fragments are highly water insoluble, clustering to yield plaques. Thus, the elimination of amyloid beta is a clear treatment goal in AD.

Significant efforts have endeavored to develop alpha agonists, or gamma- and beta-antagonists to decrease the amyloid beta burden, with no success. Recently, a monoclonal antibody that directly targets amyloid beta, has been shown to be efficient towards AD. In June 2021, the FDA approved Aducanumab-avwa (Aduhelm) co-developed by Biogen and Eisai as the first true AD drug. However, this biologic met with significant controversy. More recently another monoclonal antibody, Lecanemab-irmb (Leqembi), was granted FDA approval (January 2023). Herein, is an overview of monoclonal antibodies designed towards amyloid beta clearance, specifically targeting AD.

Early attempts

The path to the first approval of any drug for AD has been fraught with many challenges. Two medications that target the removal of excess amyloid beta: gantenerumab and bapineuzumab entered clinical studies over a decade ago, but both ultimately were deemed as failures. Gantenerumab was developed by Hoffmann-La Roche. It was a fully humanized immunoglobulin gamma 1 (IgG1) antibody designed to bind with amyloid beta fibrils. Unfortunately, Phase 3 clinical study failed to show any slowing of cognitive decline in AD, leading to halting of the trials in 2010³. Bapineuzumab was developed by Janssen and Pfizer. It was a humanized form of the murine monoclonal antibody, 3D⁶, which targeted the N-terminal region of amyloid beta. Unfortunately, trials were discontinued in 2012, due to no advantages on either cognitive or functional outcomes⁴. Both approved medications, aducanumab and lecanemab, are human IgG1 monoclonal antibodies that specifically identify aggregated forms of amyloid beta. Both have been indicated for AD patients with mild cognitive impairment (MCI) or mild dementia.

Successful ventures

Aducanumab, the first FDA-approved drug for slowing the course of AD, was initially developed utilizing the Neurimmune's Reverse Translation Medicine (RTM) technology platform. It was produced from a de-identified library of B cells taken from older people who were either cognitively impaired or exhibited cognitive decline⁵. Aducanumab specifically targets and binds to a linear epitope of amino acids 3–7 (Glu3- and Asp7-N-terminus) of soluble and insoluble amyloid beta plaques⁶. This lessens the amyloid beta plaques burden in the brain. Phase 1 (NCT01397539) and PROPEL Phase 1 (NCT02434718) clinical trials were undertaken to evaluate the safety and tolerability of IV administration of Aducanumab to establish the maximum tolerated dose, as well as the pharmacokinetics and immunogenicity of this drug. Aducanumab had reasonable safety and tolerability profiles, as well as a linear PK, at 30 mg/kg^{7, 8}. Subsequently, PRIME Phase 1b, EVOLVE Phase 2, ENGAGE Phase 3, and EMERGE Phase 3 clinical trials were implemented, but revoked due to futility analysis.

Although some trials were discontinued, Biogen launched another Phase 3 clinical trial that would run until February 20, 2025. This exclusively includes participants who had previously taken part in the terminated studies^9,10. Regardless, the ENVISION Phase 4 confirmatory trial began in June 2022 and will end in October 2026. It is a multicentered, randomized, double-blinded, placebo-controlled, parallel-group study designed to demonstrate Aducanumab's therapeutic effectiveness in AD patients. Although it has already received FDA approval, a post-approval Phase 4 confirmatory trial is necessary to confirm the anticipated therapeutic benefits. Based on prior clinical trials, there are two primary concerns: amyloid-related imaging abnormalities (ARIA) and hypersensitivity, such as angioedema and rashes. The FDA particularly recommended a brain MRI before and during therapy to identify the presence of any ARIA. ARIA patients may demonstrate as having headaches (the most common symptom; 13%), nausea, confusion, delirium, an altered mental state, disorientation, dizziness, and/or vision issues¹¹. The maintenance dose of aducanumab (10 mg/kg) has a cost of ~ $28,200/year¹². It is still debated whether or not the drug's approval was premature and its efficacy is still unclear.

Lecanemab is the most recent FDA-approved medication for AD and followed the fast-track approval pathway¹³. It works as a direct antagonist for amyloid beta aggregated soluble (protofibril) and insoluble forms, reducing plaques over time. Study 201, a Phase 2 clinical study, revealed a sufficient tolerability profile after 18 months of Lecanemab therapy. This was a Bayesian-designed multicentered, double-blinded, placebo-controlled clinical trial. Unfortunately, the primary endpoint at 12 months was not met, which required an 80% probability of greater than 25% reduction in clinical decline, compared to placebo. Moreover, the study revealed specific Lecanemab side effects, e.g., amyloid-related imaging abnormalities—edema (ARIA-E). Similar to Aducanumab, it also requires obtaining an MRI before the fifth, seventh, and fourteenth injections to monitor any ARIA events¹⁴.

Following Study 201, the Clarity AD Phase 3 confirmatory clinical trial was started in March 2019, to investigate the effectiveness, long-term safety, and tolerability of Lecanemab in people with early AD, with an anticipated study completion date of September 2027. It is a placebo-controlled, double-blinded, parallel-grouped, 18-month trial with a total of 1906 subjects. The primary outcome is to measure the change from baseline in the clinical dementia rating—sum of boxes (CDR-SB) at 18 months with secondary outcomes of change from baseline in the: Alzheimer's disease assessment scale—cognitive subscale 14 (ADAS-cog14), Alzheimer's disease composition score (ADCOMS), and Alzheimer's Disease Cooperative Study—Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL)¹⁵. Eisai and Biogen announced the findings of this ongoing investigation on November 30, 2022. The trial showcased success in its primary goal with subjects receiving lecanemab displaying a reeducation in cognitive decline on the CDR-SB by 27% at 18 months, compared to placebo. Secondary endpoints, which included amyloid plaque burden reduction, was also met with statistically significant results compared to placebo after 18 months. Lecanemab also showed a decrease in both cognitive function decline by 26% on the ADAS-Cog14 and disease progression by 24% on the ADCOMS after 18 months. Additionally, lecanemab slowed the decline in daily living activities by 37% on the ADCS MCI-ADL metric. Adverse event observed included: infusion reactions and ARIA. ARIA was further separated into ARIA-E (edema/effusion) and ARIA-H (cerebral microhemorrhages). ARIA-E occured in 12.6% of the treatment group, compared to 1.7% in the placebo group; while ARIA-H was reported in 1.4% of the treatment group and only 0.2% in the placebo group¹⁶. Of note, is no significant difference in price from aducanumab has been announced, which is reported at approximately $26,500/year in the US¹⁷.

Future endeavors

Although both aducanumab and lecanemab were approved by the FDA, they still await the outcomes of confirmatory clinical trials, ENVISION and Clarity AD, respectively. Meanwhile, others, such as Eli Lilly, are currently also attempting to bring a biologic that targets amyloid beta, to market. Solanezumab is a monoclonal antibody that works to remove amyloid proteins from the blood and cerebrospinal fluid, in an effort to prevent plaque formation. Unlike Aducanumab, it identifies only soluble monomeric amyloid beta, opposed to fibrils. In spite of Phase 1 and 2 clinical trials displaying good tolerability and safety, Phase 3 clinical trials (EXPEDITION 3) was discontinued due to failure to meet primary endpoints. However, Eli Lilly is currently conducting another Phase 3 trial (A4) to examine the drug's efficacy and establish whether Solanezumab can help decrease the progressions of memory loss caused by brain amyloid plaques. This trial is expected to conclude in June 2023¹⁸.

Eli Lilly is also developing Donanemab, a humanized IgG1 monoclonal antibody for patients in the early stages of AD. It recognizes an N-terminal pyroglutamate form of the amyloid beta epitope, which accumulates in amyloid plaques. Donanemab is designed to prevent plaque deposition and/or growth. It targets the amyloid burden that has already built up in the brain, for removal. Eli Lilly requested expedite approval, however the FDA denied this, as the required, minimum, 100 participants for at least 12 months had not been met¹⁹. Eli Lilly does have a series of TRAILBLAZER-ALZ (3, 4, and 5) Phase 3 clinical trials are underway, with the latter two expected to be completed in July 2024 and June 2027, respectively²⁰.

Remternetug is another monoclonal antibody being investigated by Eli Lilly. It recognizes pyroglutamated amyloid beta, which is present in amyloid plaques^{21, 22}. In 2022, the company conducted a Phase 3 (TRAILRUNNER-ALZ 1) randomized, double-blinded, placebo-controlled study to evaluate its safety and effectiveness in patients with early-onset symptomatic AD. The primary outcome is to measure the percentage of patients with amyloid plaques that have been cleared by the end of the treatment period with the secondary outcomes of amyloid clearance, pharmacokinetics, and anti-drug antibodies. The study is set to conclude in May 2025²³.

Outlook

Many companies continue to study and develop new medications for AD patients, such beta-secretase inhibitors and amyloid beta-targeting drugs. Aducanumab and lecanemab remain in clinical studies and are awaiting outcomes. Sadly, cholinesterase inhibitors and memantine are still the only mainstays of therapy. These do not cure, or even slow the progression of AD, but only delay symptom progression. Although the expense of new medication may end up being substantial, the need to treat the underlying causes of AD is clearly justified to those afflicted.

Reference

1.    Mayo Clinic. Alzheimer’s disease - symptoms and causes. Mayo Clinic. Published June 26, 2021. https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447
2.    Asher S, Priefer R. Alzheimer's disease failed clinical trials. Life Sci. 2022;306:120861. doi:10.1016/j.lfs.2022.120861
3.    Bateman, R.J., Cummings, J., Schobel, S. et al. Gantenerumab: an anti-amyloid monoclonal antibody with potential disease-modifying effects in early Alzheimer’s disease. Alz Res Therapy 14, 178 (2022). https://doi.org/10.1186/s13195-022-01110-8
4.    Abushouk, A.I., Elmaraezy, A., Aglan, A. et al. Bapineuzumab for mild to moderate Alzheimer’s disease: a meta-analysis of randomized controlled trials. BMC Neurol 17, 66 (2017). https://doi.org/10.1186/s12883-017-0850-1
5.    Biogen and Eisai to Discontinue Phase 3 ENGAGE and EMERGE Trials of aducanumab in Alzheimer’s Disease | Biogen. investors.biogen.com. https://investors.biogen.com/news-releases/news-release-details/biogen-and-eisai-discontinue-phase-3-engage-and-emerge-trials
6.    Arndt JW, Qian F, Smith BA, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep. 2018;8(1):6412. Published 2018 Apr 23. doi:10.1038/s41598-018-24501-0
7.    Single Ascending Dose Study of BIIB037 in Participants With Alzheimer’s Disease - Full Text View - ClinicalTrials.gov. Clinicaltrials.gov. Published 2011. https://clinicaltrials.gov/ct2/show/NCT01397539
8.    Biogen. A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of Aducanumab (BIIB037) in Japanese Subjects with Mild to Moderate Alzheimer’s Disease. clinicaltrials.gov. Published August 20, 2020. https://clinicaltrials.gov/ct2/show/NCT02434718
9.    Biogen. A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects with Early Alzheimer’s Disease. clinicaltrials.gov. Published August 7, 2020. https://clinicaltrials.gov/ct2/show/NCT02477800
10.    Biogen. A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects with Early Alzheimer’s Disease. clinicaltrials.gov. Published May 5, 2021. https://clinicaltrials.gov/ct2/show/NCT02484547
11.    Update on the Phase 4 ENVISION Confirmatory Study of ADUHELM® | Biogen. investors.biogen.com. https://investors.biogen.com/news-releases/news-release-details/update-phase-4-envision-confirmatory-study-aduhelmr
12.    Biogen Announces Reduced Price for ADUHELM® to Improve Access for Patients with Early Alzheimer’s Disease | Biogen. investors.biogen.com. https://investors.biogen.com/news-releases/news-release-details/biogen-announces-reduced-price-aduhelmr-improve-access-patients
13.    Commissioner O of the. FDA Grants Accelerated Approval for Alzheimer’s Disease Treatment. FDA. Published January 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment
14.    Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody [published correction appears in Alzheimers Res Ther. 2022 May 21;14(1):70]. Alzheimers Res Ther. 2021;13(1):80. Published 2021 Apr 17. doi:10.1186/s13195-021-00813-8
15.    van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine. Published online November 29, 2022. doi:10.1056/nejmoa2212948
16.    LECANEMAB CONFIRMATORY PHASE 3 CLARITY AD STUDY MET PRIMARY ENDPOINT, SHOWING HIGHLY STATISTICALLY SIGNIFICANT REDUCTION OF CLINICAL DECLINE IN LARGE GLOBAL CLINICAL STUDY OF 1,795 PARTICIPANTS WITH EARLY ALZHEIMER’S DISEASE | Biogen. Biogen. Published 2022. https://investors.biogen.com/news-releases/news-release-details/lecanemab-confirmatory-phase-3-clarity-ad-study-met-primary
17.    Eisai's approach to U.S. pricing for LEQEMBI™ (LECANEMAB), a treatment for early alzheimer's disease, sets forth our concept of "societal value of medicine" in relation to "Price of medicine": News release：2023. Eisai Co., Ltd. https://www.eisai.com/news/2023/news202302.html. Accessed February 4, 2023.
18.    Maria Joao Almeida. Solanezumab – Alzheimer’s News Today. Alzheimer’s News Today. Published June 12, 2017. Accessed January 27, 2023. https://alzheimersnewstoday.com/solanezumab/
19.    Company EL and. U.S. Food and Drug Administration Issues Complete Response Letter for Accelerated Approval of Donanemab. www.prnewswire.com. Accessed January 25, 2023. https://www.prnewswire.com/news-releases/us-food-and-drug-administration-issues-complete-response-letter-for-accelerated-approval-of-donanemab-301726325.html
20.    Eli Lilly and Company. A Study of Donanemab Versus Placebo in Participants at Risk for Cognitive and Functional Decline of Alzheimer’s Disease. clinicaltrials.gov. Published January 18, 2023. Accessed January 30, 2023. https://clinicaltrials.gov/ct2/show/NCT05026866
21.     Eli Lilly and Company. A Single-Dose and Multiple-Dose, Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LY3372993 in Healthy Subjects and Patients with Alzheimer’s Disease. clinicaltrials.gov. Published June 4, 2019. Accessed January 27, 2023. https://clinicaltrials.gov/ct2/show/NCT03720548?term=LY3372993&draw=2&rank=2
22.    Eli Lilly and Company. A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LY3372993 in Participants With Alzheimer’s Disease and Healthy Participants. clinicaltrials.gov. Published December 26, 2022. Accessed January 27, 2023. https://clinicaltrials.gov/ct2/show/NCT04451408?term=LY3372993&draw=2&rank=1
23.    Eli Lilly and Company. Assessment of Safety, Tolerability, and Efficacy Measured by Amyloid Reduction of LY3372993 in Early Symptomatic Alzheimer’s Disease. clinicaltrials.gov. Published January 13, 2023. Accessed January 27, 2023. https://clinicaltrials.gov/ct2/show/NCT05463731?term=LY3372993&draw=2&rank=3